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Eur J Nucl Med Mol Imaging (2009) 36:13081314 DOI 10.1007/s00259-009-1118-9
ORIGINAL ARTICLE
Saturated norepinephrine transporter occupancyby atomoxetine relevant to clinical doses: a rhesus monkey study with (S,S)-[18F]FMeNER-D2
Akihiro Takano & Balzs Gulys & Andrea Varrone &
Ralph Paul Maguire & Christer Halldin
Received: 15 January 2009 /Accepted: 2 March 2009 /Published online: 20 March 2009 # Springer-Verlag 2009
AbstractPurpose In a previous PET study on norepinephrine transporter (NET) occupancy in the nonhuman primate brain, the relationship between NET occupancy and atom-oxetine plasma concentration, and occupancies among different brain regions, were not demonstrated adequately. It may therefore be difficult to translate the results to the clinical situations. In the present study, the detailed change of NET occupancy was investigated among a wider range of doses in a more advanced manner.
Methods Two rhesus monkeys were examined using a high-resolution PET system with (S,S)-[18F]FMeNER-D2 under baseline conditions and after steady-state infusion of different doses of atomoxetine (0.003 to 0.12 mg/kg per hour). NET occupancy of the thalamus, brainstem and anterior cingulate cortex was calculated using BPND obtained with the simplified reference tissue model.
Results NET occupancy increased regionally and uniformly as the plasma concentration of atomoxetine increased. The estimated Kd value (the amount to occupy 50% of NET) in the thalamus was 16 ng/ml.
Conclusion The results indicate that clinical doses of atomoxetine would occupy NET almost completely.
Keywords Norepinephrine transporter occupancy. Atomoxetine
Introduction
The norepinephrine (NE) transporter (NET) is considered to play a key role in the pathology and treatment of neuropsychiatric diseases such as mood disorder and attention-deficit/hyperactivity disorder (ADHD) [14]. A NE reuptake inhibitor (reboxetine) has been observed to be as effective as imipramine or fluoxetine in the treatment of depression [5, 6]. Recently, a selective NE reuptake inhibitor (atomoxetine, formerly known as tomoxetine) has been found to be effective for the treatment of ADHD in both children and adults [79]. To optimize the clinical doses, measurements of receptor or transporter occupancy in vivo have been an important tool in drug development. However, in vivo NET measurement in the human brain has been hampered by the lack of suitable positron emission tomography (PET) radioligands for NET due to various factors, including high nonspecific binding of the putative ligands, lack of peak equilibrium, and high...